TY - JOUR
T1 - Oncolytic vesicular stomatitis virus and bortezomib are antagonistic against myeloma cells invitro but have additive anti-myeloma activity invivo
AU - Yarde, Danielle N.
AU - Nace, Rebecca A.
AU - Russell, Stephen J.
N1 - Funding Information:
This work was supported by National Institutes of Health grant CA100634 (to S.J.R.) and Clinical Pharmacology Training Grant T32 GM08685 (to D.N.Y.).
PY - 2013/12
Y1 - 2013/12
N2 - Multiple myeloma cells are highly sensitive to the oncolytic effects of vesicular stomatitis virus (VSV), which specifically targets and kills cancer cells. Myeloma cells are also exquisitely sensitive to the cytotoxic effects of the clinically approved proteasome inhibitor bortezomib. Therefore, we sought to determine whether the combination of VSV and bortezomib would enhance tumor cell killing. However, as shown here, combining these two agents invitro results in antagonism. We show that bortezomib inhibits VSV replication and spread. We found that bortezomib inhibits VSV-induced NF-κB activation and, using the NF-κB-specific inhibitor BMS-345541, that VSV requires NF-κB activity to spread efficiently in myeloma cells. In contrast to other cancer cell lines, viral titer is not recovered by BMS-345541 when myeloma cells are pretreated with interferon β. Thus, inhibiting NF-κB activity, either with bortezomib or BMS-345541, results in reduced VSV titers in myeloma cells invitro. However, when VSV and bortezomib are combined invivo in two syngeneic, immunocompetent myeloma models, the combination reduces tumor burden to a greater degree than VSV does as a single agent. Intratumoral VSV viral load is unchanged when mice are treated concomitantly with bortezomib compared to VSV treatment alone. To our knowledge, this report is the first to analyze the combination of VSV and bortezomib invivo. Although antagonism between VSV and bortezomib is seen invitro, analyzing these cells in the context of their host environment shows that bortezomib enhances VSV response, suggesting that this combination will also enhance response in myeloma patients.
AB - Multiple myeloma cells are highly sensitive to the oncolytic effects of vesicular stomatitis virus (VSV), which specifically targets and kills cancer cells. Myeloma cells are also exquisitely sensitive to the cytotoxic effects of the clinically approved proteasome inhibitor bortezomib. Therefore, we sought to determine whether the combination of VSV and bortezomib would enhance tumor cell killing. However, as shown here, combining these two agents invitro results in antagonism. We show that bortezomib inhibits VSV replication and spread. We found that bortezomib inhibits VSV-induced NF-κB activation and, using the NF-κB-specific inhibitor BMS-345541, that VSV requires NF-κB activity to spread efficiently in myeloma cells. In contrast to other cancer cell lines, viral titer is not recovered by BMS-345541 when myeloma cells are pretreated with interferon β. Thus, inhibiting NF-κB activity, either with bortezomib or BMS-345541, results in reduced VSV titers in myeloma cells invitro. However, when VSV and bortezomib are combined invivo in two syngeneic, immunocompetent myeloma models, the combination reduces tumor burden to a greater degree than VSV does as a single agent. Intratumoral VSV viral load is unchanged when mice are treated concomitantly with bortezomib compared to VSV treatment alone. To our knowledge, this report is the first to analyze the combination of VSV and bortezomib invivo. Although antagonism between VSV and bortezomib is seen invitro, analyzing these cells in the context of their host environment shows that bortezomib enhances VSV response, suggesting that this combination will also enhance response in myeloma patients.
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U2 - 10.1016/j.exphem.2013.09.005
DO - 10.1016/j.exphem.2013.09.005
M3 - Article
C2 - 24067362
AN - SCOPUS:84888864862
SN - 0301-472X
VL - 41
SP - 1038
EP - 1049
JO - Experimental Hematology
JF - Experimental Hematology
IS - 12
ER -